Molecular Psychiatry (2008) 13, 918–929

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FEATURE REVIEW

Antipsychotic drug mechanisms: links between

therapeutic effects, metabolic side effects and the
insulin signaling pathway
RR Girgis1,2, JA Javitch1,2 and JA Lieberman1,2
1
Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA and 2New York
State Psychiatric Institute, New York, NY, USA

The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent
evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially
associated with metabolic side effects compared to first-generation antipsychotic drugs
(FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their
comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the
insulin signaling pathway is vital for normal brain development and function. Abnormalities of
this pathway have been found in persons with schizophrenia and antipsychotic drugs may
ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic
antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a
common pharmacologic mechanism. This article reviews insulin metabolism in the brain and
related abnormalities associated with schizophrenia with the goals of gaining insight into
antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia.
Finally, we speculate about one potential mechanism of action (that is, functional selectivity)
that would be consistent with the data reviewed herein and make suggestions for the future
investigation that is required before a therapeutic agent based on these data can be realized.
Molecular Psychiatry (2008) 13, 918–929; doi:10.1038/mp.2008.40; published online 15 April 2008
Keywords: antipsychotic; functional selectivity; insulin; mechanism of action; metabolic side
effects; schizophrenia

Introduction generation antipsychotic drugs (FGAs; for example,

Schizophrenia is a chronic, debilitating psychiatric
illness characterized by positive, negative and cogni-
tive symptoms.1 Antipsychotic drugs have been the
primary treatment for approximately half of a century,
beginning with the discovery and introduction of
chlorpromazine.2 However, despite the extensive use
and study of these agents, questions remain regarding
their exact mechanism of action.3 Much of the study
to date has focused on the receptor profiles of these
medications.3 Interest in dopamine-2 (D2) receptor
blockade stemmed, in part, from evidence that there
existed a close relationship between the potency of
conventional agents at the dopamine receptor and
clinical potency.4,5 Serotonergic and glutamatergic
mechanisms have also been implicated, in part,
because of the perceived advantages of the second-
generation antipsychotic drugs (SGAs; for example,
risperidone and olanzapine) compared to the first-
Correspondence: Dr RR Girgis, Department of Psychiatry, College
of Physicians and Surgeons, Columbia University, 1051 Riverside
Drive, Box 109, New York, NY 10032, USA.
E-mail: rg2290@columbia.edu
Received 21 October 2007; revised 20 February 2008; accepted 10
March 2008; published online 15 April 2008
haloperidol and chlorpromazine) and because of the
schizophrenia-like symptoms that occur when sub-
stances of abuse targeting these receptors are used.3,6,7
Nevertheless, although many theories have been
proposed, no antipsychotic effect has been observed
in an agent without D2 receptor affinity,8 with the
exception of the very recent data suggesting anti-
psychotic properties of an mGlu2/3 receptor agonist.9
The uncertainty regarding the precise mechanisms
of action of antipsychotic drugs, and in particular the
role of serotonin antagonism, has been compounded
by the recent data that suggest that SGAs, with the
possible exception of clozapine and to a lesser extent
olanzapine, have not been wholly proven to be more
effective than FGAs.10–14 Further complicating the
efforts by clinicians and researchers to understand the
neurochemical and cellular modifications necessary
for an antipsychotic effect is the lack of a complete
understanding of the pathogenesis, pathophysiology
and genetics of schizophrenia.7
The objective of this article is to review the evidence
and propose a plausible basis for a unitary mechanism
of action for the differential metabolic and therapeutic
effects of antipsychotic drugs. This will be fundamen-
tally based upon clinical observations of the positive

relationship between the effectiveness of antipsycho-
tic drugs and their proclivity for metabolic side effects
(that is, primarily for SGAs). We hypothesize that the
therapeutic and adverse metabolic effects of anti-
psychotic drugs (as typified by clozapine and olanza-
pine) are related. We also suggest that there are
abnormalities of the insulin signaling pathway in
schizophrenia that are affected by antipsychotic drugs.
Several lines of evidence support this hypothesis.
We first describe the relationship between the com-
parative effectiveness and metabolic disturbances
of antipsychotic drugs, which forms the basis for the
hypothesis of this article. Thereafter, this article
focuses on the role of the insulin signaling pathway
in neurodevelopment and brain function, new data on
interactions between the dopamine and N-methyl-D-
aspartate (NMDA) systems and the insulin signaling
pathway, abnormalities of the insulin signaling path-
way in the brains of individuals with schizophrenia
and the data indicating that antipsychotic drugs can
ameliorate some of these deficits. Finally, we specu-
late how one mechanism of action (that is, functional
selectivity, a phenomenon by which ligands that bind
to the same receptor can differentially recruit intra-
cellular signaling pathways15) could account for the
positive relationship between the effectiveness of
antipsychotic drugs and their proclivity for metabolic
side effects and discuss implications for future
research and clinical practice.
The relationship between the comparative
effectiveness and metabolic disturbances of
antipsychotic drugs
With the introduction of clozapine and demonstration
of its superior efficacy when compared to FGAs16
came the hope that subsequent SGAs would also
exhibit superior efficacy. Although this was largely
thought to be the case, recent data suggest that there is
less clinical difference in effectiveness between FGAs
and SGAs than previously believed, with the possible
exceptions of clozapine and, to a lesser extent,
olanzapine (Table 1).10–13,17
Table 1 Comparisons between second-generation anti-
psychotics on effectiveness, degree of metabolic disturbances
and magnitude of effects on glycogen synthase kinase
Clinical and Comparisons between SGAs
biochemical measures
Effectiveness Clz > OlzXRispIQuetIZipIAri
Degree of metabolic ClzXOlz > RispIQuetXZipIAri
disturbances
Magnitude of effects ClzIOlz > RispIQuetXZip
on GSK
Abbreviations: Ari, aripiprazole; Clz, clozapine; GSK,
glycogen synthase kinase; Olz, olanzapine; Quet, quetia-
pine; Risp, risperidone; SGAs, second-generation anti-
psychotic drugs; Zip, ziprasidone.
Antipsychotic drug mechanisms
RR Girgis et al
919
However, there are several distinguishing charac-
teristics between FGAs and SGAs. High-affinity and
sustained D2 receptor blockade is overtly responsible
for some of the major side effects (that is, extra-
pyramidal side effects, EPS) of FGAs and, to some
degree, antipsychotic activity.4,8,18 By contrast, cloza-
pine, the prototype SGA, has relatively low affinity
for the D2 receptor, induces few to no EPS and is
considered to possibly be the most effective anti-
psychotic, but has a high liability for precipitating
metabolic disturbances.11,19,20 In addition, it has
become apparent that several other SGAs, in addition
to clozapine, have a marked propensity to induce
metabolic disturbances, including hyperglycemia,
hyperlipidemia, obesity, insulin resistance and some-
times frank diabetes mellitus.20–23
Following the introduction of chlorpromazine and
the first neuroleptics, EPS were thought to be a
prerequisite for antipsychotic efficacy.2,24 Clozapine
and other SGAs violated this principle by having
antipsychotic efficacy with little or no EPS,3 hence
the term ‘atypical’ antipsychotic. Subsequently, SGAs
were observed to have an increased risk of metabolic
side effects. Therefore, if one considers the relation-
ship between potency (that is, of dopamine receptor
antagonism) and clinical efficacy of FGAs in relation
to their ability to produce EPS, one might similarly
consider a relationship between potency (that is, of
a nontraditional mechanism of action) and efficacy
of SGAs in relation to their ability to produce
metabolic side effects. Although this apparent asso-
ciation between antipsychotic efficacy and metabolic
side effects liability could be coincidental, it is also
possible that they are due to a common mechanism.
What mechanism could be responsible for this
relationship? As all antipsychotic drugs are dopamine
receptor blockers but only some of them produce
metabolic side effects and to significantly varying
degrees, this would implicate either selective inter-
actions with the dopaminergic system missed
by current methods of visualizing receptor occu-
pancy and drug–receptor interactions or an extra-
dopaminergic mechanism. However, to date there is
no explanation of alternative therapeutic mechanisms
of action beyond D2 receptor blockade that involve
any other neuroreceptor, with the exception of the
very recent data suggesting antipsychotic properties
of an mGlu2/3 receptor agonist,9 even though theories
involving the 5-HT2A, 5-HT1A and NMDA receptors,
among others, have been proposed.3 Hence, there is
great interest in examining novel or nontraditional
mechanisms of action that could explain the superior
efficacy of clozapine and olanzapine and their side
effect liabilities.
Such speculation is reinforced by the striking
realization that the most effective of the SGAs (that
is, clozapine and olanzapine) have the greatest
metabolic side effect liabilities, followed variably
by quetiapine and risperidone, although ziprasidone
and aripiprazole are least implicated in these
effects (Table 1).20,25,26 However, this is not meant to
Molecular Psychiatry
 Antipsychotic drug mechanisms
RR Girgis et al
920
oversimplify the relationship between schizophrenia
and disturbances in glucose metabolism. In fact, this
relationship is quite complex and not well under-
stood.27 For example, although evidence suggests
that the prevalence of diabetes mellitus is high in
individuals with schizophrenia, there is debate27 as
to whether abnormalities in glucose metabolism are
actually present at the first episode28 or develop in the
course of the illness, which complicates understand-
ing the precise contribution of antipsychotic drugs
to alterations in glucose metabolism in individuals
with schizophrenia. Nevertheless, it is clear that the
increased use of SGAs is associated with increasing
rates of diabetes mellitus.21 Therefore, the recognition
of this intriguing relationship between the thera-
peutic efficacy and magnitude of metabolic distur-
bances of SGAs warrants examination and is the basis
for the hypothesis of this paper that the therapeutic
and metabolic side effects of antipsychotic drugs are
related.
Possible mechanisms of antipsychotic-induced
disordered glucose metabolism
Before discussing the possible mechanisms of anti-
psychotic-induced disturbances in glucose meta-
bolism, we briefly review the metabolic side effects
of antipsychotic medications. SGAs have been asso-
ciated with clinically significant weight gain, some-
times greater than 20 lb with higher doses of
olanzapine.29,30 Some have also been associated with
increased levels of blood glucose, glycosylated hemo-
globin and insulin, along with insulin resistance, and
sometimes frank type 2 diabetes mellitus.29,30 Finally,
some SGAs have been associated with unfavorable
effects on blood lipid profiles, such as increased total
cholesterol, low-density lipoprotein, and triglyceride
levels and decreased levels of high-density lipopro-
tein levels.29,30 In general, clozapine and olanzapine
have been most associated with these preceding
adverse effects, followed variably by risperidone and
quetiapine, whereas ziprasidone and aripiprazole
have been associated with the least or no such
adverse metabolic risks.29,30
Although hyperglycemia, insulin resistance, hyper-
lipidemia and obesity are all aspects of the metabolic
profiles of SGAs, the focus of this hypothesis is on the
phenomena of hyperglycemia and insulin resistance
given the fundamental role that glucose utilization
and the insulin signaling pathway play in normal
brain development and function along with the
pathophysiology of schizophrenia (as discussed in
the following sections). This is done with the under-
standing that these various metabolic disturbances
are likely related, rather than isolated, occurrences.31
As with the association between schizophrenia
and diabetes mellitus, the mechanism of disordered
glucose metabolism associated with SGAs is not
clearly understood32 and is likely multifactorial.
One suggested mechanism of these disturbances is
via inhibition of glucose transporters.32,33 Impaired
Molecular Psychiatry
glucose regulation centrally and peripherally, along
with associated alterations in insulin production
in the pancreas, may also contribute.32–35 Alteration
of the phosphoinositide-3-kinase (PI3K)/Akt insulin
signaling pathway is another potential mechanism.33
Interactions between antipsychotic drugs and seroto-
nergic, histaminergic, muscarinic and a-adrenergic
receptors along with leptin might also contribute to
these phenomena, either primarily or as secondary
effects on weight and/or adiposity.32,34,36 Some of
these mechanisms, such as blockade of histamine-1
receptors37 and inhibition of glucose transport,38–40
are correlated with antipsychotic-associated meta-
bolic disturbances, such as their potential to induce
orexigenic effects and hyperglycemia. Of these poten-
tial mechanisms, the insulin signaling cascade has
been implicated in the pathophysiology of schizo-
phrenia and is targeted by antipsychotic drugs and
will therefore be the focus of this paper.
Insulin, insulin-like growth factor and the insulin
signaling pathway
The insulin and insulin-like growth factor (IGF)-1
receptors share common evolutionary origins and
have similar structures and signaling pathways.41
IGF-1 receptor expression in the brain begins as early
as neural tube development, and IGF-1 and insulin
receptor expression become widespread, particularly
in neurons.41 Abnormalities of IGF have been sug-
gested to make individuals more susceptible to
schizophrenia,42 possibly by making those who
already have a predisposition to schizophrenia more
vulnerable to environmental insults during neuro-
development.43
The effects of insulin/IGF are mediated by a
signal transduction cascade, beginning with a tyro-
sine kinase receptor (Figure 1).44 After insulin binds
the extracellular aspect of its receptor, a conforma-
tional change takes place, which results in autophos-
phorylation of the receptor.44 Multiple different
insulin receptor substrates transmit the signal to
different effectors in the cell, such as PI3K.44 Several
of the lipid products of PI3K activate another group
of kinases, such as Akt and protein kinase C (PKC),
which are highly implicated in glucose metabolism
and transport and the effects of insulin.44
Akt, also known as protein kinase B, requires
phosphorylation for activation.44 Akt has a variety of
effects in the cell including regulation of the cell
cycle, regulation of cell death as an antiapoptotic
factor and DNA synthesis.45 The PI3K/Akt pathway has
also been implicated as a mediator of the effects of
neuregulin, a gene that has been associated with
schizophrenia,46 on neuronal development and survi-
val.47 Interestingly, Akt1-deficient mice show abnormal
dendritic architecture of layer V of their prefrontal
cortex.48 These mice also exhibit impaired working
memory under D2, but not dopamine-1 (D1), challenge.48
The significance of these findings is underscored by
the abnormalities in dendritic architecture and working

Figure 1 A simplified version of the insulin signaling
pathway. Insulin or insulin-like growth factor (IGF) binds to
the insulin/IGF receptor causing autophosphorylation and
activation. This leads to activation of phosphoinositide-
3-kinase (PI3kinase), and the end result is to phosphorylate
and activate Akt and phosphorylate and deactivate glycogen
synthase kinase-3 (GSK-3). Active GSK-3 deactivates glyco-
gen synthase and eukaryotic initiation factor 2B (eIF2B) and
activates insulin receptor substrate-1 (IRS-1; an inhibitor of
the insulin receptor). PIP3, phosphoinositide 3,4,5-tris-
phosphate; PKC, protein kinase C (adapted and modified
with permission from Gould and Manji49).
memory, along with the potential role of the D2
receptor, in schizophrenia.1 Finally, Akt appears to
be associated with the trafficking of glucose trans-
porters to the neuronal membrane.41
Another substrate of Akt is glycogen synthase
kinase (GSK). GSK has been associated with mood
stabilization and implicated as a possible target of
lithium.49 More recently, GSK has been associated
with schizophrenia as well.50,51 GSK is expressed
widely throughout the human brain and is observed
as early as embryonic day 10 in rats.52 Two isoforms
(GSK-3a and b) have been identified52 that are
constitutively active.49 In the PI3K/Akt pathway, Akt
Antipsychotic drug mechanisms
RR Girgis et al
921
phosphorylates GSK-3a at Ser21 and GSK-3b at
Ser9, resulting in their inhibition.53 Cholinergic,
serotonergic and glutamatergic neurotransmission,
also implicated in the pathophysiology of schizo-
phrenia, may also regulate the phosphorylation state
of GSK (reviewed in Jope and Roh50).
GSK has multiple effects on both neurodevelop-
ment and glucose metabolism.52 Through the PI3K/
Akt pathway GSK is involved in neurotrophic
effects49 and the regulation of apoptosis.52 GSK also
influences other crucial neuronal processes including
neural plasticity, microtubule dynamics, neurite
outgrowth, neurogenesis and transcription factors/
gene expression (for example, via transcription factors
such as cyclic AMP response element-binding pro-
tein).50 GSK is one of the main mediators of the Wnt
signaling cascade, which is important in synaptic
arrangement and neural tube development/pattern-
ing.52 Interestingly, preliminary findings suggest that
components of the Wnt pathway may be abnormal in
schizophrenia (reviewed in Jope and Roh50). Further-
more, the protein products of approximately 10 genes
that have been associated with schizophrenia (for
example, Akt1, disrupted in schizophrenia-1 (DISC1),
NRG1) appear to be involved in GSK signaling.51
Finally, GSK has effects on glucose and insulin
metabolism as inhibition (that is, phosphorylation)
of GSK activates glycogen synthase, which leads to
the synthesis of glycogen.49,52
In summary, in addition to its well-established role
in maintaining euglycemia, the insulin signaling
pathway and its components may be significant in
neuronal growth, synaptic development and neuronal
survival/apoptosis during brain development. There-
fore, alterations of this pathway may have profound
implications for the pathogenesis, pathophysiology
and treatment of neurodevelopmental disorders of the
brain.
The role of the insulin signaling pathway in
schizophrenia: insights from the dopamine
and NMDA receptor hypofunction hypotheses
Traditionally, dopamine receptors have been asso-
ciated with G-protein regulation and cyclic AMP/
protein kinase A signaling.54 Recently, a cyclic AMP-
independent mechanism of dopaminergic behaviors
and signaling at the D2 receptor was identified, which
involves the Akt/GSK pathway.54 The model used was
dopamine transporter (DAT) knockout mice, which
have increased availability of dopamine and exhibit
hyperactive behaviors and stereotypic movements.55
DAT knockout mice had decreased levels of both
phospho-Thr308-Akt, phospho-Ser21-GSK-3a and
phospho-Ser9-GSK-3b in their striatum, abnormali-
ties which were ameliorated by dopamine depletion
and by D2 (but not D1) receptor antagonism.55 Remark-
ably, inhibition of GSK-3 in DAT knockout mice
also inhibited the dopamine-dependent behaviors.55
Finally, dopamine agonism decreased the phosphoryla-
tion of both Akt and GSK-3 in normal mouse striatum,
Molecular Psychiatry
 Antipsychotic drug mechanisms
RR Girgis et al
922
Figure 2 Working model of the Akt/b-arrestin 2 (bArr2)/
protein phosphatase 2A (PP2A) signaling complex formed
in response to activation of dopamine (DA) receptors (D2R)
leading to Akt inactivation in the mouse striatum (adapted
and modified with permission from Beaulieu et al.56).
and GSK-3b mutant mice had reduced behavioral
response to dopamine agonism.55
Later research elucidated the mechanism of D2
receptor-mediated Akt regulation (Figure 2).56
Namely, the binding of dopamine to the D2 receptor
leads to the formation of a complex consisting of
b-arrestin 2, Akt and protein phosphatase 2A.56
b-Arrestin 2 serves as a scaffold for both Akt and
protein phosphatase 2A, thereby facilitating dephos-
phorylation of Akt.56
Data from studies on the effects of NMDA receptor
antagonists on the insulin signaling pathway also
indicate abnormalities of insulin signaling in schizo-
phrenia.57 Phencyclidine (PCP) or ketamine use can
lead to schizophrenia-like symptoms in humans.58 In
neuronal culture, PCP can be toxic.57 In rats, PCP
administration led to decreased phospho-Ser473-Akt
but stable total Akt in frontal cortex, hippocampus
and striatum.57 Similar results were observed in rat
neuronal culture,57 indicating that PCP leads to
decreased activity of Akt. Activating L-type calcium
channels (which favors cell survival) or NMDA
receptors blocked both PCP-induced neurotoxicity
and reduction in phospho-Ser473-Akt.57 In both
cases, adding a specific inhibitor of Akt restored the
neurotoxicity of PCP, indicating that the PI3K/Akt
pathway was primarily responsible for protecting
against the PCP-induced neurotoxicity.57 As expected,
PCP administration also led to decreased phospho-
Ser9-GSK-3b in rat frontal cortex, hippocampus and
striatum, along with in rat neuronal culture and no
change in total GSK-3b, indicating increased activity
of GSK-3b.57 Selective inhibition of GSK-3b elimi-
nated the neurotoxic effects of PCP57 again implicat-
ing a role for this pathway in the neurotoxic effects of
PCP.
The next sections of this article review the reported
abnormalities of the insulin signaling pathway in
schizophrenia and how antipsychotic drugs may
ameliorate these alterations and possibly lead to
therapeutic efficacy in schizophrenia. However,
based on the data presented to this point, several
Molecular Psychiatry
predictions can be made. First, an overactive dopa-
minergic system in schizophrenia,1 or hypofunction
of the NMDA system,58 would predictably lead to
decreased phosphorylation and activity of Akt and
decreased phosphorylation and increased activity of
GSK. For antipsychotic drugs (that is, D2 receptor
antagonists) to be effective, they would predictably
have to reverse these effects (that is, lead to increased
phosphorylation and activity of Akt and increased
phosphorylation and decreased activity of GSK).
Abnormalities of the insulin signaling pathway in
schizophrenia and how antipsychotic drugs might
affect these alterations
The data on the insulin signaling pathway in schizo-
phrenia and the effects of antipsychotic drugs are
complicated for several reasons. First, human studies
often involve subjects who have already been exposed
to a variety of FGAs and/or SGAs. In addition, the
presence or absence of the disease state (that is,
schizophrenia) potentially complicates the compar-
ison and analysis of studies involving human neuro-
pathologic or cell culture data. Further, comparisons
are required between human and nonhuman data
and between studies involving different cell types.
Finally, issues regarding specimen processing (as
discussed below)50,59 add another level of complexity
to the interpretation of this data. In spite of these limi-
tations, a review of the available studies is informa-
tive. Inconsistencies and confounded effects will be
identified and discussed as they are presented.
The insulin receptor, phosphoinositides and protein
kinase C
Genetic alterations of various components of the PI3K
pathway have been reported in individuals with
schizophrenia,60 including in Chinese61 and African
American62 populations. Relationships between other
components of phosphoinositide signaling, such as
phosphatidylinositol-4-phosphate 5-kinase II-a (PIP5-
K2A), with schizophrenia have also variably been
observed,63,64 though one study of IGF-1 in Caucasian
populations did not find any association with
schizophrenia.65
There is little neuropathologic data suggesting
abnormalities of the more proximal components of
the insulin signaling pathway. In a sample of indi-
viduals with schizophrenia, all of whom had been
treated with FGAs, except for one who had been on
clozapine, a neuropathologic examination showed
decreased density of PKC in the parahippocampus
when compared to controls, with no correlation
between PKC density and antipsychotic dose.66 In a
similar analysis, no differences were found in the
striatum,67 or in the platelets of another group of
individuals with schizophrenia when PKC activity
was compared to that in control subjects.68 In addi-
tion, while haloperidol exposure in rats increased the
activity of PKC in the frontal cortex in one investiga-
tion,69 another demonstrated that rats treated with

4 weeks of haloperidol or clozapine had no changes in
PKC levels in frontal cortex, basal ganglia or olfactory
tubercle.70 These data indicate little correlation
between antipsychotic drugs and the proximal com-
ponents of the insulin signaling pathway and there-
fore corroborate observations that the interaction
between the D2 receptor/antipsychotic drugs and the
insulin signaling pathway may occur at the level
of Akt.56 Although another study suggests that PKC
is involved in the augmenting effects of clozapine
on NMDA signaling in pyramidal cells of the medial
prefrontal cortex,71 this study did not specifically
address the interaction of this phenomenon with the
insulin signaling pathway.
Other data are consistent with a state of insulin
resistance and hyperinsulinemia after treatment with
antipsychotic drugs. Olanzapine has been shown to
inhibit the insulin-stimulated activation of PI3K in
a rat skeletal muscle cell line72 and upregulates
insulin-2 in rat frontal cortex.73 In addition, Zhao
et al.74 examined the insulin receptor in dorsolateral
prefrontal cortex from individuals with schizophre-
nia, most of whom had been receiving FGAs and
several of whom had been receiving SGAs. Both the
total and activated amounts of the insulin receptor
were found to be reduced in these individuals.74
Akt
Akt and schizophrenia. The potential relevance of
genetic abnormalities of Akt1 in individuals with
schizophrenia was strongly supported by the find-
ing that an Akt1 haplotype associated with lower
levels of Akt1 was related to schizophrenia in
a Northern European population.75 Positive relation-
ships between Akt1 and schizophrenia were also
reported in Caucasian,76 Iranian,77 Japanese78 and
Chinese79 populations, but not in two other Japanese
populations59,80 or a Taiwanese population,81 and
variably in a Caucasian population.82 In addition,
undertransmission of some haplotypes of Akt1 was
found in an Irish sample.83
There is limited data on Akt in schizophrenia. In
addition, the phosphorylation level of Akt is closely
related to the peri-mortem condition of the tissue
(for example, temperature, pH),59 which could serve
as a potential confound of these data. However, the
available data suggest decreased levels of total and
phosphorylated Akt in schizophrenia, which is
consistent with theories of schizophrenia that postu-
late overactive dopaminergic systems in mesolimbic
areas of the brain1 or NMDA receptor hypofunction.58
One study examined dorsolateral prefrontal cortex
from individuals with schizophrenia, most of whom
had been receiving FGAs and several of whom had
been receiving SGAs, and demonstrated decreased
levels of both total and phospho-Ser473-Akt.74 Simi-
lar decreases in Akt1 expression were found in
dorsolateral prefrontal cortex in another sample,83
whereas other studies reported no alterations in
frontal cortex Akt159,84 or phosphorylated Akt in
Antipsychotic drug mechanisms
RR Girgis et al
923
individuals with schizophrenia.59 Meanwhile, Ema-
mian et al.75 observed decreased levels of total Akt1
in lymphocyte-derived cell lines, frontal cortex
and hippocampus from individuals with schizophre-
nia. Finally, in primary neuronal culture, inhibition
of DISC1, a gene implicated in schizophrenia, led
to decreased phosphorylation of Akt but stable levels
of total Akt.85
Akt and antipsychotic drugs. In contrast to the effects
of DISC1 inhibition, clozapine has been reported to
increase phosphorylation of Akt in neuroblastoma
cells.86 A similar analysis in mouse neuroblastoma
cells demonstrated that 5 days of both clozapine
and chlorpromazine increased phospho-Ser473-Akt
without increasing total Akt levels.87 Olanzapine has
been similarly shown to increase levels of phospho-
Ser473-Akt in PC12 cells although total Akt remained
the same.88 This effect was dependent on PI3K,
suggests an additional mechanism of antipsychotic
effects on Akt and may be related to differences in cell
line.88 Chronic treatment of mice with haloperidol did
not alter the total levels of Akt1 in the frontal cortex
but did increase phosphorylated Akt1 at both Thr308
(acute and chronic) and Ser473 (chronic only).75 This
was consistent with a study of mice treated with
clozapine for 68 days in which although insulin
receptor activity and Akt levels were decreased, the
amount, and thus activity, of phospho-Ser473-Akt was
unchanged.74
Curiously, chlorpromazine, clozapine and fluphe-
nazine did not lead to increased phosphorylation of
Akt in PC12 cells.88 In another study, fluphenazine,
chlorpromazine and haloperidol decreased the
nerve growth factor-induced phosphorylation of Akt
at Ser473 in PC12 cells,89 which is consistent with
another study that showed that acute haloperidol
treatment of rat neurons decreased levels of phospho-
Ser473-Akt.90 These data begin to underscore and
elucidate differences in efficacy between antipsycho-
tic drugs (that is, more effects on Akt of olanzapine
and clozapine than other antipsychotic drugs). How-
ever, these data are limited by the nearly cytotoxic
doses of antipsychotic drugs used in some of these
experiments,34,91 which may contribute to their
discrepant effects on Akt.
Although most of the preceding data suggest that
SGAs generally increase levels of phosphorylated
Akt, opposite effects were noted in glioblastoma cells
in which clozapine inhibited Akt phosphorylation,92
possibly due to differences in cell line. In a rat
skeletal muscle cell line, olanzapine inhibited the
insulin-stimulated phosphorylation of Akt,72 which is
consistent with a state of peripheral insulin resis-
tance; a known side effect of olanzapine.29
In summary, at least in a number of studies, anti-
psychotic drugs appear to increase phosphorylation of
Akt. These effects are antagonistic to what occurs in
schizophrenia (that is, decreased Akt phosphorylation)
and predictable based on both the dopamine and
NMDA receptor hypofunction hypotheses.
Molecular Psychiatry
 Antipsychotic drug mechanisms
RR Girgis et al
924
GSK
GSK and schizophrenia. Although genetic
relationships have been reported between GSK-3b
and the paranoid subtype of schizophrenia in an
Italian population93 and marginally so in a Chinese
population,94 significant relationships were not found
for schizophrenia in general in Italian,93 Finnish,95
Japanese,96 Chinese94 and Korean97 populations.
Multiple investigations have examined the levels
and activities of GSK-3 isoforms in individuals with
schizophrenia and in animal models. The data
suggest decreased levels and increased activity of
GSK-3 in schizophrenia. These results are consistent
with the data reviewed above showing decreased
activity of Akt and are consistent with predictions
based on the dopamine and NMDA receptor hypo-
function hypotheses of schizophrenia.1,58 However,
the results of studies of GSK in schizophrenia are
mixed. This is not unexpected for the reasons
discussed previously, as well as because the study
of GSK in post-mortem tissues is highly problematic
given the marked changes in phosphorylation state
that occur post mortem and in response to anesthesia
(that is, in nonhuman brain tissue).50,59 Nevertheless,
the available data are informative and are reviewed
below.
In one neuropathologic study of individuals with
schizophrenia, bipolar disorder and unipolar depres-
sion, only the individuals with schizophrenia had
decreased levels of GSK-3b and decreased activity of
GSK-3 in frontal cortex, whereas no alteration in the
level of GSK-3b in occipital cortex was observed.98,99
In addition, no correlation was noted between life-
time antipsychotic exposure and GSK-3b levels.98
These results are consistent with a later study
showing that GSK-3b mRNA, but not GSK-3a mRNA,
levels were decreased in the dorsolateral prefrontal
cortex from individuals with schizophrenia compared
with a comparison group of normal controls, indivi-
duals with bipolar disorder and individuals with
unipolar depression; no correlations were noted with
lifetime antipsychotic consumption, and no differ-
ences were noted between those individuals treated
and not treated with lithium.100 When the phosphor-
ylation levels of GSK-3b at Ser9 (that is, the site
phosphorylated by Akt1) were measured in frontal
cortex and lymphocytes from individuals with schi-
zophrenia, decreased levels were found, although
levels of the GSK-3b form phosphorylated at Tyr216
were not abnormal in either the lymphocytes or
frontal cortex.75 Other neuropathologic studies of
individuals with schizophrenia reported that GSK-
3b levels were decreased in the prefrontal cortex from
these individuals101 and that phospho-Ser9-GSK-3b
levels were decreased in the frontal cortex of
these individuals.84 Decreased levels of GSK-3b
were also observed in the cerebrospinal fluid of indi-
viduals with schizophrenia, with no correlation
with antipsychotic dose.102 Zhao et al.74 examined
dorsolateral prefrontal cortex from individuals with
Molecular Psychiatry
schizophrenia, most of whom had been receiving
FGAs and several of whom had been receiving SGAs,
and found increased levels of total GSK-3 (a and b)
while the phosphorylated forms of both enzymes
remained unaltered, indicating increased activity of
these enzymes.74
Data from animal studies have supported and
extended these abnormalities of GSK in schizo-
phrenia. In rats exposed to hippocampal damage,
reduced frontal GSK-3b levels were observed prior to
but not after puberty, whereas no differences at either
age were observed in total GSK-3 (a and b) activity.103
This is of particular relevance to schizophrenia
because of the robust evidence suggesting abnor-
malities of the hippocampus in schizophrenia.104 A
study of GSK-3b levels in rat frontal cortex showed no
response to acute or chronic stress, suggesting that the
altered GSK-3b levels observed in schizophrenia may
be disease related and not a nonspecific stress
response.105 Similarly, rats exposed to 21 days of
haloperidol, chlorpromazine or clozapine had no
alterations in GSK-3b levels or total GSK-3 (a and b)
activity in their frontal cortex,106 again suggesting that
the changes observed in patients were not simply a
response to antipsychotic treatment.
However, other neuropathologic and biochemical
studies have found inconsistent results. Two such
investigations found no differences in GSK-3b in
prefrontal cortex of individuals with schizo-
phrenia.107,108 A third study reported no abnormalities
of GSK-3a or -b mRNA levels, GSK-3b protein levels
or total GSK-3 (a and b) activity in frontal cortex from
individuals with schizophrenia, but did find reduc-
tions in these measures in hippocampus (that is,
GSK-3b protein levels only after omitting outliers).109
Similarly, no alterations in frontal cortex GSK-3b
or phosphorylated GSK-3b were found in a recent
study of individuals with schizophrenia.59 Finally,
no differences in GSK-3a and -b mRNA, GSK-3b
protein or GSK-3 (a and b) activity were observed
in the lymphocytes of individuals with schizo-
phrenia.75,110
GSK and antipsychotic drugs. Recent investigations
in animal models have indicated that antipsychotic
drugs have important effects on GSK. Subchronic
treatment of rats with haloperidol and risperidone,
but not clozapine, increased GSK-3 protein levels in
striatum, whereas all three of these drugs increased
GSK-3 protein levels in the prefrontal cortex and
ventral midbrain.111,112 In addition, subchronic halo-
peridol and risperidone increased phospho-Ser9-GSK-
3b levels in the prefrontal cortex, whereas chronic, but
not acute, haloperidol and risperidone also increased
GSK-3 (a and b) levels in prefrontal cortex and ventral
midbrain, indicating that repeated treatment may
be necessary for the observed changes.111,112 Further,
as with Akt1, chronic treatment with haloperidol
increased the levels of phospho-Ser9-GSK-3b in
mice.75 In another study, rats treated with haloperidol
had decreased phospho-Ser9-GSK-3b in frontal cortex

whereas those treated with clozapine had increased
levels.113 As noted previously, the discrepancy bet-
ween these two studies may be related to the different
animal models used (rats versus mice), the different
doses of haloperidol used (10 versus 1 mg kg
1), the
different lengths of exposure in each study (21 versus
12 days)75,113 or confounds related to the use
of anesthetic agents and post-mortem processing of
tissues.50
Li et al.114 showed that one dose of risperidone,
but not haloperidol, increased phospho-Ser9-GSK-3b
and phospho-Ser21-GSK-3a levels in mouse cortex,
striatum (not significant for GSK-3a), hippocampus
and cerebellum, although total GSK-3b remained
the same.114 Some of the effects of risperidone
were augmented by co-treatment with imipramine or
fluoxetine.114 Further, no effects of risperidone were
noted on either phospho-Ser473-Akt or phospho-
Thr308-Akt, suggesting that the Akt pathway was
not involved,114 a finding inconsistent with previous
data. In the same study, a similar analysis
was performed comparing the effects of clozapine,
olanzapine, quetiapine and ziprasidone on phospho-
Ser9-GSK-3b levels in the brains of mice and found
that clozapine and olanzapine had the greatest effect,
followed by quetiapine, whereas ziprasidone had the
least effect.114 Interestingly, these results are consis-
tent with data that suggest that clozapine and
olanzapine are the most likely of the SGAs to cause
metabolic disturbances and are possibly also the most
effective (Table 1).12–14,20,25,26
Antipsychotic drugs have been found to have
mixed effects on GSK in different cell and tissue
culture environments. Clozapine has been found to
increase levels of phospho-Ser9-GSK-3b in neuro-
blastoma cells.86 Similar results were observed in
another study of mouse neuroblastoma cells exposed
to 5 days of antipsychotic; active, nonphosphorylated
GSK-3b decreased after exposure to both chlorproma-
zine and clozapine.87 In mice that had been treated
with clozapine for 68 days it was observed that
although insulin receptor activity decreased and
phospho-Ser21-GSK-3a and phospho-Ser9-GSK-3b
remained the same, total GSK-3a and -b levels, and
thus activity, were decreased.74 Opposite effects were
noted in glioblastoma cells in which clozapine had
the effect of dephosphorylating GSK-3b at Ser9,92
possibly related to differences in cell line. Olanzapine
inhibited the insulin-stimulated phosphorylation
(that is, inactivation) of GSK-3 (a and b) in a rat
skeletal muscle cell line.72 Though apparently
discrepant with previous findings in neural cells,
this phenomenon would be consistent with a state
of peripheral insulin resistance; a known side effect
of olanzapine.29
In summary, the effect of antipsychotic drugs on
GSK is relatively consistent and is to increase
phosphorylation (and inactivation). This is consis-
tent with predictions based on the dopamine and
NMDA receptor hypofunction hypotheses of schizo-
phrenia.
Antipsychotic drug mechanisms
RR Girgis et al
925
Summary of the abnormalities of the insulin signaling
pathway in schizophrenia and the effects of
antipsychotic drugs
In summary, there are limited and mixed data on the
insulin signaling pathway in schizophrenia and how
antipsychotic drugs interact with it. Further, as stated
above, the synthesis and analysis of this data is
complicated by a number of important factors. Never-
theless, several general observations and speculations
can be made. First, limited genetic analyses have
implicated alterations in Akt1, certain phosphoinosi-
tide-related genes and GSK-3b in some populations
of individuals with schizophrenia. Second, the data
on inherent abnormalities of the insulin signaling
pathway in schizophrenia are inconclusive for multi-
ple reasons, not the least of which is prior anti-
psychotic exposure, though they suggest decreased
levels of Akt, phosphorylated Akt and GSK, along
with increased activity of GSK, in schizophrenia.
Antipsychotic drugs appear in most cases to increase
phosphorylation levels of Akt and GSK, thereby
decreasing the activity of GSK. These observations
are strikingly consistent with the known operation of
the insulin signaling pathway (Figure 1). They are
also consistent with both the overactive dopaminergic
stimulation and NMDA receptor hypofunction hypo-
thetical models of schizophrenia. In addition, anti-
psychotic drugs appear to reverse these abnormalities.
Finally, although both FGAs and SGAs have been
implicated in these effects, preliminary evidence
suggests that these effects might occur more or to a
greater degree with SGAs and in particular for those
SGAs that are considered to be both the most effective
and to be the most associated with metabolic distur-
bances (that is, clozapine, and, to a lesser extent,
olanzapine; Table 1). Altogether, these data support
our hypothesis that the unique therapeutic and
adverse effects of antipsychotic drugs (and in parti-
cular clozapine and olanzapine) are related and
suggest that the insulin signaling pathway may be
one focal point for such a phenomenon. However, the
relevance of the insulin signaling pathway for the
effects of antipsychotic drugs remains speculative.
Functional selectivity as an example of a potential
mechanism for coupling antipsychotic drug
therapeutic and metabolic side effects
Much investigation is needed before a compelling
unitary mechanism of antipsychotic drug action for
therapeutic efficacy and metabolic side effects can be
put forward. However, the fact that antipsychotic
drugs with the greatest efficacy have the greatest
metabolic effects is curious and prompts speculation.
In addition, the recent findings that the D2 receptor
and antipsychotic drug effects are intertwined with
the insulin signaling pathway may be relevant and
make speculation about a potential unitary mecha-
nism of action possible.
One possibility is that clozapine and olanzapine
have different targets than other antipsychotic drugs,
Molecular Psychiatry
 Antipsychotic drug mechanisms
RR Girgis et al
926
and therefore D2 receptor blockade is irrelevant to
their antipsychotic effect. This seems unlikely given
that no antipsychotic effect has been observed in any
agent without D2 receptor affinity,8 with the exception
of the very recent data suggesting antipsychotic
properties of an mGlu2/3 receptor agonist.9 Alterna-
tively, although D2 receptor blockade may still be
required for their therapeutic effects, these drugs may
gain their superior response profile by acting at a non-
D2 receptor target, such as at histamine-1,37 seroto-
nergic or muscarinic receptors.36 Another possibility
is that different antipsychotic drugs selectively inter-
act with the D2 receptor in ways that lead to
differences in signaling but are missed by our current
methods of visualizing receptor occupancy and drug–
receptor interactions. This model suggests that it is
the ability of an antipsychotic drug to enhance
signaling via the insulin signaling pathway (that is,
via Akt/GSK) rather than traditional D2 receptor
mechanisms (that is, via the cyclic AMP pathway)
that leads to greater efficacy. Similarly, this model
suggests that these unique, qualitative interactions
between antipsychotic drugs and the D2 receptor,
by contrast to their quantitative interactions (for
example, potency or strength of stimulus which
would suggest ‘all-or-nothing’ effects on signaling
pathways),15 may more clearly explain their differ-
ential therapeutic effects. This would also contribute
to our understanding of why the medications that are
more prone to affect this pathway (for example,
clozapine, olanzapine) are also more associated with
metabolic side effects, with the caveat that this might
be one of multiple factors affecting proclivity for
metabolic side effects, as reviewed above.
The notion that the binding of different psychotropic
agents to the same G-protein-coupled receptor can
cause different behavioral and physiologic effects is
intriguing but not novel. Indeed, evidence has begun to
emerge suggesting that ligands may be able to induce
different and selective conformational changes in their
receptors, which in turn leads to the recruitment of
different signaling pathways.15,115,116 Structurally dis-
tinct ligands may also be able to differentially activate
signaling pathways based on the existence of certain
key signal transducing proteins, such as arrestins,117
proteins also involved in D2 receptor signaling.56 This
phenomenon has been given numerous names, includ-
ing ‘functional selectivity,’ ‘agonist-directed trafficking
of receptor stimulus,’ ‘biased agonism’ and ‘stimulus
trafficking,’15,116 and investigative techniques, such as
transcriptome analysis,115 are already being used to
address these effects. In particular, functional selecti-
vity has been observed at the D2 receptor.15,118 How-
ever, to our knowledge, no studies to date have
explored the functional selectivity of D2 receptor
signaling as the basis for the effects of antipsychotic
drugs on the Akt/GSK signaling pathway. Therefore,
although this phenomenon is intriguing, its pertinence
remains unclear.
On the basis of the information presented herein,
several directions of future inquiry can be suggested.
Molecular Psychiatry
First and foremost is the need to develop a better
characterization of the insulin signaling pathway
in schizophrenia. One way to do this, in addition
to neuropathologic examination, would be to use
cerebrospinal fluid and/or the peripheral tissues of
neuroleptic-naive patients.51 The use of peripheral
tissues would be feasible given the relative consis-
tencies that have been reported between measures in
peripheral tissues and cerebrospinal fluid with
neuropathologic data.75,102 Obtaining such measures
both before and after treatment with antipsychotic
drugs and other pharmacologic compounds known to
affect the insulin signaling pathway (for example,
lithium) would also shed light on the effects of anti-
psychotic drugs on this pathway. Our understanding
of the degree to which antipsychotic drugs participate
in functional selectivity could also be assessed in cell
culture by exposing D2 receptor-expressing cells to
antipsychotic drugs at clinically therapeutic concen-
trations and measuring the amounts and activities
of various components of the different dopamine
signaling pathways (for example, cyclic AMP/protein
kinase A pathway, Akt/GSK pathway). Finally, the
roles of the dopamine and glutamate systems, along
with other neurotransmitter systems (for example,
serotonergic, cholinergic) implicated in schizo-
phrenia, on the insulin signaling pathway need to
be further clarified to understand the likely complex
role of these pathways in schizophrenia and before
drug development targeted at this pathway can be
most efficiently accomplished and understood.
Conclusions and therapeutic implications
In summary, there is a variety of evidence that sup-
ports the hypothesis that the therapeutic and adverse
effects of antipsychotic drugs (and in particular
clozapine and olanzapine) are related. These data
also suggest that there exist abnormalities of the
insulin signaling pathway in schizophrenia and that
antipsychotic drug effects on this pathway are
therapeutic in schizophrenia. Importantly, this hypo-
thesis was developed based on clinical observations
of the differential therapeutic effectiveness and
proclivity for metabolic side effects of SGAs and
appears to be consistent with current hypotheses
about the role of the dopamine and NMDA receptor
systems in the pathophysiology and treatment of
schizophrenia. However, the data that associate
antipsychotic action with the insulin signaling
pathway remain preliminary and sometimes contra-
dictory.
The development of this hypothesis based on a
theoretical unitary mechanism of therapeutic and
metabolic side effects is not meant to, nor could
it, fully explain two likely complicated and multi-
factorial phenomena. For example, our hypothesis
does not fully explain the development of peripheral
insulin resistance. It remains unclear whether it is the
presence of the disease state (that is, schizophrenia),
the presence or absence of D2 receptors, or some other

RR Girgis et al
mechanism that explains why antipsychotic drugs
have therapeutic effects centrally and detrimental
effects peripherally. Rather, this hypothesis and
article are meant to assemble relevant basic science,
translational and clinical data with the hope of
providing a theoretical framework for one potential
avenue of future drug development. Given the range
of effects that components of the insulin signaling
pathway may have on neurodevelopment and brain
function, it is possible that any one of these may have
an important role in antipsychotic effects. Further
investigation is crucial to foster the much-needed
development of novel pharmacologic agents based on
these observations.
Acknowledgments
This work was supported in part by grants from the
NIH and from the Lieber Center for Schizophrenia
Research and Treatment. We thank Dr Karen Duff for
her helpful comments on this paper.
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